Background: Phenylketonuria is often called PKU. Mothers face multiple problems because they are playing a vital role in caring for sick children for long time, thus helping decreasing strain and promoting health for maintain their wellbeing. Aim: This study aimed to evaluate the effects of coping strategies intervention on strain and quality of life among mothers of children with phenylketonuria. Method: a quasi-experimental design was conducted in out-patient clinics and genetics department affiliated to Mansoura University Children's Hospital (MUCH), involving 48 mothers of children diagnosed with phenylketonuria. Data were collected using a structured interviewing questionnaire sheet, mother knowledge about PKU, Coping Inventory for Stressful Situation (CISS), Modified Caregiver Strain Index (MCSI) and the WHO Quality of Life-BREF (WHOQOL-BREF). Results: The current study reveals that enhancing coping strategies after applying the study intervention. The mean of mothers 'coping strategies in posttest was higher than in the pretest (193.43 ± 9.26 & 79.8±7.2respectively) with a statistically significant difference between the two-study intervention. Also, there was a highly statistically significant negative correlation between pre- and post- coping score and strain level (r=-0.298, p<0/001; r=-0.401, p<0.001) and between pre and post quality of life and strain level among mothers having children with PKU (r=-0.234, p<0.001; r=-0.352, p<0.001) and the positive correlation between coping and QOL pre and post intervention (r=0.332, p<0.001; r=0.463, p<0.001). Conclusion: The study concluded that, coping strategies intervention had a positive effect on reducing strain and improving quality of life among mothers of children with PKU.  Recommendations: the specialist can educate the mother how to adapt by using coping strategies when caring child with PKU, especially those who have a positive family history and doing regular training about using coping strategies.